It has long been known that excessive mitotic activity due to H-Ras can block keratinocyte differentiation and cause skin cancer. It is not clear whether there are any innate surveillants that are able to ensure that keratinocytes undergo terminal differentiation, preventing the disease. IKK&amp;#945;induces keratinocyte terminal differentiation and its reduction promotes skin tumor development. However, its intrinsic function in skin cancer is unknown. Thus, our lab generated Ikk&amp;#945;conditional knockout mice, deleted IKK&amp;#945;in keratinocytes in mice by using keratinocyte specific Cre mice, and then examined the effect of IKK&amp;#945;loss on skin development and maintenance, and skin tumorigenesis. We found that mice with IKK&amp;#945;deletion in keratinocytes developed a thickened epidermis and spontaneous squamous cell-like carcinomas. Inactivation of epidermal growth factor receptor (EGFR) or reintroduction of IKK&amp;#945;inhibited excessive mitosis, induced terminal differentiation, and prevented skin cancer through repressing an EGFR-driven autocrine loop. We also identified that IKK&amp;#945;repressed expression of several EGFR ligands at their transcription level, thereby inhibiting the pathway of EGFR and Ras. Thus, IKK&amp;#945;serves as an innate surveillant. These findings shed light on therapeutic targets for preventing IKK&amp;#945;-related skin cancer development.